Docosahexaenoic Acid Protects Traumatic Brain Injury by Regulating NOX₂ Generation via Nrf2 Signaling Pathway

Docosahexaenoic acid (DHA) is verified to have neuroprotective effects on traumatic brain injury (TBI) rats by activating Nrf2 signaling pathway, but the role of NOX₂ in this effect has not been illuminated. So this study explored the role of NOX₂ in TBI models treated with DHA, aiming to complete the mechanism of DHA. TBI rat models were constructed with or without DHA treatment, and H₂O₂-induced hippocampal neurons were pretreated with DHA alone or in combination with Nrf2 inhibitor brusatol. The neurological function, cognitive ability, and cerebral edema degree of rats were assessed. The apoptosis rate and viability of cells was measured. The generation of NOX₂, Nrf2, HO-1 and NQO-1 expression levels, and ROS content in hippocampal CA1 region and hippocampal neurons were detected. DHA could not only improve the neurological function, brain edema and cognitive ability in TBI rats, but also decrease effectively the contents of NOX₂ and ROS in hippocampal CA1 region and hippocampal neurons. DHA promoted the nuclear transposition of Nrf2 and the expression levels of HO-1 and NQO-1 in hippocampal CA1 region and hippocampal neurons. On the contrary, Nrf2 inhibitor brusatol inhibited the nuclear transposition of Nrf2 and the expression levels of HO-1 and NQO-1 in hippocampal neurons, promoted the generation of ROS and NOX₂, and accelerated cell apoptosis. Both in vivo and in vitro experiments demonstrated that DHA treated TBI by reducing NOX₂ generation that might function on Nrf2 signaling pathway, providing a potential evidence for its clinical application.